Calcineurin activity is required for depolarization-induced, CREB-dependent gene transcription in cortical neurons.
- Resource Type
- Article
- Authors
- Kingsbury, Tami J.; Bambrick, Linda L.; Roby, Clinton D.; Krueger, Bruce K.
- Source
- Journal of Neurochemistry. Oct2007, Vol. 103 Issue 2, p761-770. 10p. 1 Black and White Photograph, 8 Graphs.
- Subject
- *PROTEIN binding
*BIOCHEMISTRY
*CARRIER proteins
*BIOLOGICAL transport
*CALCIUM-binding proteins
*GENETIC regulation
*IMMUNOSUPPRESSIVE agents
- Language
- ISSN
- 0022-3042
Cyclic AMP response element binding protein (CREB) functions as an activity-dependent transcription factor in the nervous system. Increases in intracellular Ca2+ due to neuronal activity lead to the phosphorylation and subsequent activation of CREB. Although phosphorylation of CREB at Ser-133 is necessary for the stimulation of transcriptional activity, it is not sufficient. Here we demonstrate that in mouse cortical neurons, inhibition of the Ca2+-dependent protein phosphatase calcineurin by FK506 or cyclosporine A blocks CREB-dependent gene expression induced by depolarization without inhibiting depolarization-induced Ca2+ influx or CREB Ser-133 phosphorylation. Over-expression of a constitutively-active allele of the transducer of regulated CREB activity could not bypass the requirement for calcineurin activity. Stimulation of a CRE-luciferase reporter gene by depolarization was sensitive to FK506 throughout the entire time course of the transcriptional response, revealing that calcineurin activity is required to maintain CREB-dependent transcription. Stimulation of CRE-luciferase expression by forskolin and 8-Br-cAMP also required calcineurin activity. These results suggest that calcineurin functions as a critical determinant in shaping genome responses to CREB activation in cortical neurons. [ABSTRACT FROM AUTHOR]